CN102706954B - Spin Valve GMR membrane structure, the biosensor with it and manufacture method - Google Patents

Abstract

The present invention proposes a spin valve giant magnetoresistance GMR thin film structure, comprising: a substrate; a buffer layer formed on the substrate; a composite free layer sequentially formed on the buffer layer; An isolation layer on the composite free layer, the isolation layer is a non-magnetic material; a pinned layer formed on the isolation layer; a pinned layer formed on the pinned layer; formed on the An overburden layer above the pinned layer. The invention has high magnetoresistivity and good coercive force, improves the detection limit of biomolecule concentration, and can be mass-produced and applied. The invention also provides a biological sensor and its manufacturing method, a multi-channel scanning circuit detection system and a biological detection method.

Description

Spin-valve GMR film structure, biosensor with same and manufacturing method

technical field

The invention relates to the fields of microelectronics and medical technology, in particular to a spin-valve GMR thin film structure, a biosensor with it, a method for making the biosensor, a multi-channel scanning circuit detection system with the biosensor, and a biodetection method.

Background technique

Magnetic biosensor technology is prepared based on various magnetoresistance effects. It senses the weak magnetic signal generated by a certain concentration of biomolecular magnetic markers, and converts the magnetic signal into an electrical signal, thereby realizing the qualitative and quantitative detection of the biomolecules to be tested. a new technology. Since Professor Fert's research group discovered the GMR effect in 1988, the applied research based on this effect has developed rapidly, and has become an international example of the rapid transformation of basic research into commercial applications. Compared with traditional detection methods such as fluorescence detection, GMR (Giant MagnetoResistive, giant magnetoresistance) biosensors have strong anti-interference ability and are more adaptable to harsh detection environments and background interference. Whether it is the performance of the sensor itself or the characteristics of the magnetic label, the research on the GMR sensor array in the field of biological detection has high application value and practical significance.

The world's first GMR biosensor device is a magnetic ball array counter (BeadArrayCounter, BARC) developed by Baselt et al. in the US Naval Research Laboratory (NRL). Although the first generation of GMR biosensor chip is very primitive, it has shown good specificity and sensitivity, the signal with magnetic label is more than 10 times higher than the background signal without magnetic label, and this sensor has shown field detection and multi- Potential for object detection. At present, the National Naval Laboratory of the United States, the research group of Stanford University and the Philips research group of the Netherlands are in the leading position in the world in the research of GMR biosensors.

At present, many universities and research institutes in China are also devoted to the research of GMR biosensors, and have achieved many achievements in the production technology of multilayer film and spin valve GMR film. However, due to the limitations of the research environment and conditions, the performance of the prepared GMR film cannot reach the ideal level. The circuit detection system is simple and rough, and they all stay at the level of using the GMR sensor to detect the surface magnetic balls, and have not really achieved magnetic label immunity. The detection technology of immobilizing active biomolecules on the surface of the sensor and then collecting and processing the magnetic ball signal, therefore, there is currently no practical product of magnetically labeled GMR biosensors, which are used in the diagnosis of diseases in the medical field.

Contents of the invention

The purpose of the present invention is to solve at least one of the above-mentioned technical drawbacks.

Therefore, the first object of the present invention is to provide a spin-valve giant magnetoresistance GMR thin film structure, which has good performance. The second object of the present invention is to provide a biosensor. The third object of the present invention is to provide a method for fabricating a biosensor. The fourth object of the present invention is to provide a multi-channel scanning circuit detection system. The fifth object of the present invention is to provide a biological detection method.

In order to achieve the above object, the embodiment of the first aspect of the present invention proposes a spin-valve giant magnetoresistance GMR film structure, comprising: a substrate; a buffer layer formed on the substrate; sequentially formed on the buffer layer The composite free layer above; the isolation layer formed on the composite free layer, the isolation layer is a non-magnetic material; the pinned layer formed on the isolation layer; the pinned layer formed on the a pinned layer over a layer; a capping layer formed over said pinned layer.

The spin-valve giant magnetoresistance GMR thin film structure according to the embodiment of the present invention has high magnetoresistance, good coercive force, improved detection limit of biomolecular concentration, and can be mass-produced and applied.

The embodiment of the second aspect of the present invention proposes a biosensor, including: the spin valve GMR thin film structure provided by the embodiment of the first aspect of the present invention, the metal wire formed on the spin valve GMR thin film structure, and the spin valve GMR covering A film structure and a passivation layer partially covering the metal wire; a bioaffinity layer formed on the passivation layer.

The biosensor according to the embodiment of the second aspect of the present invention adopts a composite passivation layer structure, which not only effectively protects the sensor surface from solution erosion, but also ensures the detection sensitivity of the system, and can be mass-produced.

The embodiment of the third aspect of the present invention provides a method for manufacturing a biosensor, comprising the following steps:

providing a substrate, and cleaning the substrate;

forming a spin valve GMR thin film on the substrate, and etching the spin valve GMR thin film to form the spin valve GMR thin film structure described in the embodiment of the first aspect of the present invention;

Metal wires connected to the spin valve GMR thin film structure;

forming a passivation layer covering the spin valve GMR film structure and the metal wire;

forming a bioaffinity layer over the passivation layer; and

Etching the passivation layer and the bioaffinity layer to expose a portion of the metal wire.

According to the manufacturing method of the biosensor according to the embodiment of the present invention, the composite passivation layer structure is adopted, which not only effectively protects the surface of the sensor from solution erosion, but also ensures the requirements of the detection sensitivity of the system, and the manufacturing technology is stable and the operation steps are simple, which can mass production applications.

The embodiment of the fourth aspect of the present invention provides a multi-channel scanning circuit detection system, including the biosensor provided according to the embodiment of the second aspect of the present invention, a multi-channel detector, and the multi-channel detector is connected to the biosensor; A multiplexer, the multiplexer is connected with the multi-channel detector; a low noise amplifier, the low noise amplifier is connected with the multiplexer; a bandpass filter, the bandpass filter is connected with the multiplexer The low noise amplifier is connected; and a LabVIEW controller, the LabVIEW controller is used to control the multi-channel detector and the multiplexer.

According to the fourth aspect of the present invention, the multi-channel scanning circuit detection system provided by the embodiment has the characteristics of high signal-to-noise ratio, high sensitivity, and good stability, and can accurately reflect the influence of the magnetic sensor on the magnetoresistance change of the fringe field of the nano-magnetic ball. In addition, the multi-channel scanning detection method is adopted, and LABVIEW is used to realize the control, which can effectively control the system status and output, and display the output voltage signal in real time. The technology is stable, the operation steps are simple, and it can be mass-produced and applied.

The embodiment of the fifth aspect of the present invention provides a biological detection method, comprising the steps of:

Combining the biomolecules to be tested with magnetic nanospheres to form biomolecules to be tested with magnetic labels;

immobilizing the biomolecules to be tested carrying the magnetic label on the surface of the biosensor according to the embodiment of the second aspect of the present invention; and detecting the fringe field response signal of the magnetic nanosphere, and The field response signal is converted into a corresponding voltage signal to detect the concentration of the biomolecule to be detected.

According to the biological detection method of the embodiment of the present invention, nano magnetic balls are used to label immunologically active molecules, and the response signal of the GMR magnetic sensor to the magnetic balls is used to reflect the detection method of the concentration of biomolecules. This detection platform can measure the concentration of various biomolecules. The detection and interval estimation, and the technology is stable, the operation steps are simple, and can be applied in mass production.

Additional aspects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention.

Description of drawings

The above and/or additional aspects and advantages of the present invention will become apparent and easy to understand from the following description of the embodiments in conjunction with the accompanying drawings, wherein:

1 is a schematic diagram of a spin valve GMR thin film structure according to an embodiment of the present invention;

FIG. 2 is a flow chart of a biosensor fabrication method according to an embodiment of the present invention;

Fig. 3a is a schematic structural diagram of photolithography stage I according to an embodiment of the present invention;

Fig. 3b is a schematic structural diagram of photolithography stage II according to an embodiment of the present invention;

FIG. 3c is a schematic structural diagram of stage III of photolithography according to an embodiment of the present invention;

Fig. 3d is a schematic structural diagram of photolithography stage IV according to an embodiment of the present invention;

4 is a schematic diagram of a multi-channel scanning circuit detection system according to an embodiment of the present invention;

5 is a flow chart of a biological detection method according to an embodiment of the present invention; and

Fig. 6 is a structural diagram of a magnetic label biosensor according to an embodiment of the present invention.

detailed description

Embodiments of the present invention are described in detail below, examples of which are shown in the drawings, wherein the same or similar reference numerals designate the same or similar elements or elements having the same or similar functions throughout. The embodiments described below by referring to the figures are exemplary only for explaining the present invention and should not be construed as limiting the present invention.

The following disclosure provides many different embodiments or examples for implementing different structures of the present invention. To simplify the disclosure of the present invention, components and arrangements of specific examples are described below. Of course, they are only examples and are not intended to limit the invention. Furthermore, the present invention may repeat reference numerals and/or letters in different instances. This repetition is for the purpose of simplicity and clarity and does not in itself indicate a relationship between the various embodiments and/or arrangements discussed. In addition, various specific process and material examples are provided herein, but one of ordinary skill in the art will recognize the applicability of other processes and/or the use of other materials. Additionally, configurations described below in which a first feature is "on" a second feature may include embodiments where the first and second features are formed in direct contact, and may include additional features formed between the first and second features. For example, such that the first and second features may not be in direct contact.

In the description of the present invention, it should be noted that unless otherwise specified and limited, the terms "installation", "connection" and "connection" should be understood in a broad sense, for example, it can be a mechanical connection or an electrical connection, or it can be two The internal communication of each element may be directly connected or indirectly connected through an intermediary. Those skilled in the art can understand the specific meanings of the above terms according to specific situations.

These and other aspects of embodiments of the invention will become apparent with reference to the following description and drawings. In these descriptions and drawings, some specific implementations of the embodiments of the present invention are specifically disclosed to represent some ways of implementing the principles of the embodiments of the present invention, but it should be understood that the scope of the embodiments of the present invention is not limited by this limit. On the contrary, the embodiments of the present invention include all changes, modifications and equivalents coming within the spirit and scope of the appended claims.

The structure of a spin-valve giant magnetoresistance GMR thin film according to an embodiment of the present invention will be described below with reference to FIG. 1 .

As shown in FIG. 1 , the spin-valve GMR thin film structure of the embodiment of the present invention includes a substrate 101, a buffer layer 102 formed on the substrate 101, a composite free layer sequentially formed on the buffer layer 102, and a composite free layer formed on the composite layer. The isolation layer 105 over the free layer, the pinned layer 106 formed over the isolation layer 105, the pinned layer 107 formed over the pinned layer 106, and the cover layer 108 formed over the pinned layer 107 .

In an embodiment of the present invention, the material of the substrate 101 may be polished glass. The glass itself is insulated and does not need additional oxidation to form an insulating layer, so that the cost of the experiment can be saved, and the manufacturing process is simple.

In an embodiment of the present invention, the isolation layer 105 may be a non-magnetic material. Wherein, the isolation layer 105 includes copper Cu. The thickness of the isolation layer 105 is 1.8 nm. The non-magnetic material Cu separates the two magnetic layers, and the two magnetic layers have a certain coupling effect through the Cu layer.

In one embodiment of the invention, cap layer 108 includes tantalum Ta. Wherein, the thickness of the covering layer 108 is 3 nm. In addition to its function as a buffer layer, Ta also has a protective function. Sputtering a layer of Ta on the top of the entire spin valve film can protect the underlying functional layer and prevent the spin valve from being corroded and oxidized.

In yet another embodiment of the present invention, the pinning layer 107 includes IrMn, such as Ir19Mn81, IrMn has a higher failure temperature, a smaller feature thickness, a higher exchange bias field, and good corrosion resistance. annealing. The pinned layer 106 includes CoFe, such as Co90Fe10. CoFe has a large coercive force.

Wherein, the pinned layer 106 has a thickness of 3.5 nm, and the pinned layer 107 has a thickness of 11 nm.

In one embodiment of the present invention, the composite free layer includes a first free layer 103 and a second free layer 104 , wherein the first free layer 103 includes NiFe, and the second free layer 104 includes CoFe. Wherein, the thickness of the composite free layer is 5.5 nm.

The coercivity of NiFe and CoFe is relatively small, the saturation field is relatively low, and a small external magnetic field can reverse its magnetization direction. Inserting a thin layer of Co90Fe10 (at%) to separate the two can ensure that interlayer diffusion does not occur and improve spin-dependent scattering at the interface. Among them, Co-Fe should not be too thick.

In one embodiment of the invention, the buffer layer 102 includes β-Ta. Wherein, the buffer layer 102 is a seed layer with a thickness of 5 nm. β-Ta greatly improves the texture of the metal thin films grown on it, thereby improving the performance of the spin valve, so Ta is selected as the material of the buffer layer.

In one embodiment of the present invention, the pinned layer 107 may be a top pinned layer or a bottom pinned layer, that is, the pinned layer may be located above or below the composite free layer. Specifically, the pinned layer above the composite free layer is called the top pinned layer, and the pinned layer below the composite layer is called the bottom pinned layer. The giant magnetoresistance GMR film structure of the bottom pinned layer, because the free layer is closer to the sensor surface than the top pinned spin valve film, the response effect of the prepared sensor to the magnetic ball will be improved.

However, in the absence of annealing, the lattice texture of the antiferromagnetic material growth of the spin valve structure of the top pinned layer is better than that of the antiferromagnetic material growth of the bottom pinned spin valve structure. Therefore, the spin valve performance is more ideal after the thin film sputtering is completed.

Moreover, for the spin-valve GMR film structure of the top pinning layer, the customized four-step photolithography process scheme and layout design can successfully prepare GMR films with excellent performance, high magnetoresistance, small coercive force, Large linear range.

The spin-valve giant magnetoresistance GMR thin film structure according to the embodiment of the present invention has high magnetoresistance, good coercive force, improved detection limit of biomolecular concentration, and can be mass-produced and applied.

The embodiment of the second aspect of the present invention provides a biosensor, including the spin valve GMR thin film structure provided in the embodiment of the first aspect of the present invention, the metal wire formed on the above spin valve GMR thin film structure, covering the above spin valve The GMR film structure and the passivation layer partially covering the metal wires form a bioaffinity layer on the passivation layer.

In one embodiment of the present invention, the passivation layer is SiO2 and the bioaffinity layer is Au.

Specifically, the SiO2 passivation layer was prepared by the PECVD method at 200 ° C to generate a growth SiO2 thin film, and then sputter Ti20nm/Au50nm on the surface of the signal unit by the lift-off process as a bioaffinity layer to grow biological probes. For the signal unit, a composite layer passivation structure of SiO2 and Ti/Au is used, and biological probes can be immobilized on the gold film by biochemical methods, thus providing a biological interface.

Then spin-coat a layer of SU-8 glue with a thickness of 2 μm outside the signal unit on the surface of the silicon wafer, and remove the SU-8 glue covering the signal unit through photolithography and development. Finally, the sensor was heated at 180° C. for 10 minutes to cure the SU-8 glue, thereby completing the preparation of the passivation layer of the sensor. For the sensing unit of the reference unit, it is protected by a composite structure of SiO2 and SU-8 glue, which not only meets the requirements for the normal operation of the biosensor in a liquid environment, but also effectively shields the edge field of the magnetic ball from affecting the reference unit in the bridge sensor. Impact.

The passivation layer can prevent solution corrosion in a liquid environment and protect the internal structure of the sensor. At the same time, the detection object of the GMR biosensor is the edge field of the magnetic ball. The larger the distance between the magnetic ball and the free layer of the spin valve, the smaller the output signal of the biosensor. it is good.

The biosensor according to the embodiment of the present invention adopts a composite passivation layer structure, which not only effectively protects the surface of the sensor from solution erosion, but also ensures the detection sensitivity requirements of the system, and has stable manufacturing technology, simple operation steps, and can be mass-produced and applied .

The method for fabricating the biosensor provided by the embodiment of the third aspect of the present invention will be described below with reference to FIG. 2 .

As shown in Figure 2, the method for manufacturing a biosensor provided by an embodiment of the present invention includes the following steps:

Step S201, providing a substrate and cleaning the substrate.

In step S2011 , cleaning the substrate 302 used for the first time is performed according to the following steps, wherein the substrate 301 may be a silicon wafer, as shown in FIG. 3 a .

(1) Use recycled sulfuric acid: hydrogen peroxide = 4:1 ratio solution to immerse the silicon wafer, boil until there are no bubbles, for example, boil for about 2 minutes.

(2) Rinse with cold water for 1 minute + hot water for 2 minutes + cold water for 2 minutes.

(3) Use No. I solution [deionized water: hydrogen peroxide (30%): ammonia water (28%) = 5:2:1] and boil for two minutes.

(4) Rinse with cold water for 1 minute + hot water for 2 minutes + cold water for 2 minutes.

(5) New sulfuric acid: hydrogen peroxide = 4:1 ratio solution immerse Si slices and boil.

(6) Rinse with cold water for 1 minute + hot water for 2 minutes + cold water for 2 minutes.

(7) Bake on the electric stove for 20 minutes, and perform the next step.

In an embodiment of the present invention, the following step is further included: oxidizing the substrate 302 to form an insulating substrate 307 .

In step S2012 , the Si sheet is then oxidized to form an insulating substrate 307 . The silicon wafer should be cleaned without stains and water marks. When oxidizing, the silicon wafer should be placed in the quartz boat to keep it standing naturally in the quartz boat to avoid stress caused by oxidation. Silicon wafers oxidized using a dry-wet-dry process. The thickness of the oxide layer is greater than 600nm, which is suitable for the manufacture of linear GMR sensors.

Step S202 , forming a spin-valve GMR thin film on the substrate, and etching the spin-valve GMR thin film to form the spin-valve GMR thin film structure of the embodiment of the first aspect of the present invention.

In step S2021, the DC magnetron sputtering system sputters the spin valve thin film.

Pay attention to the relationship between the crystal orientation of the silicon wafer and the direction of the induced magnetic field during sputtering. For example, when using a Si (100) substrate, the notch edge of the crystal orientation of the Si wafer should be perpendicular to the direction of the induced magnetic field. The choice of coating program can be determined according to actual needs.

Step S2022, photolithography I, forming a spin valve magnetoresistive strip mask 301, as shown in FIG. 3a.

The purpose of photolithography I is to form a mask for the IBE (IonBeamEtching, ion beam etching) etching process. The photoresist can be thinner when spinning the glue, such as 1.2 microns. After development, the film needs to be hardened to improve the photoresist mask. anti-etching capability.

Step S2023, ion beam etching (IBE).

In another embodiment of the present invention, the following step is further included: etching the spin-valve GMR film at intervals by ion beam etching.

Ion beam etching is a dry patterning method, and a companion film should be prepared before etching to ensure thorough etching within the selected etching time. During etching, the ion beam energy is usually selected as 300eV or 500eV. In order to prevent the thermal deformation of the photoresist, the etching should be carried out in a few times and many times. For example, each etching takes 1.5 minutes and rests for 2 minutes, for a total of 6 etchings. Before etching, it should be checked whether the direction of the magnetoresistive strips in the photolithographic pattern is consistent with the crystal direction of the silicon wafer, and whether it is etched through after etching.

In one embodiment of the present invention, check whether it is cut through by one or both of the following methods:

(1) Observe the color of the Si oxide layer with a microscope;

(2) Measure the conductivity with a multimeter.

If there is a problem, it needs to be re-lithographic.

Step S2024, removing glue.

To remove the photoresist used as a mask in photolithography I, the following methods can be used: soaking with acetone, or using 80w power ultrasonic assist for a period of time to speed up the glue removal speed. After stripping is complete, check for residual photoresist. If there is residual photoresist, rinse with alcohol or wipe with cotton ball to remove residual photoresist.

Step S203, forming metal wires connected to the spin valve GMR thin film structure.

Step S2031, photolithography II, forming metal wires.

Photolithography for the "positive resist stripping" process usually uses positive resist, and the thickness of the photoresist should be ensured to be greater than 2 microns. During development, it is treated with chlorobenzene (about 1 minute), so that the edge of the photoresist can be peeled off sharply. After development, it is not used for post-baking hardening film treatment, which is convenient for the operation of the "positive resist stripping" process.

Step S2032, DC sputtering thick Al layer, thereby forming a metal Al wire 303, as shown in FIG. 3b.

In order to ensure good contact between Al and the spin valve film before sputtering, the surface of the spin valve film needs to be cleaned by oxygen plasma to remove the residual positive resist in the second photolithography. On the premise of not affecting the performance of the GMR membrane, the time for degumming is preferably about 20 minutes. After the deglue is completed, it is necessary to perform reverse etching on the surface of the spin valve to remove the oxide layer structure on the surface, so that a good contact is formed between the spin valve film and the wire.

In step S2033, the positive resist is stripped to complete the patterning of the metal structure.

Positive resist stripping refers to the method of removing the film (metal film or oxide film) on the photoresist by using an organic solution such as acetone to dissociate the photoresist. When positive resist stripping is used, the thickness of the photoresist should be at least 2 to 3 times the thickness of the stripped film. The specific peeling method is to soak in acetone solution for a long time until the peeled film is cracked, separated, and peeled off in a large area. The film remaining on the silicon wafer can be completely removed with the aid of ultrasonic equipment. In order not to damage the film structure, the ultrasonic power Choose 80w, and the ultrasonic time depends on the removal of the film. For more firmly adhered films, wipe off carefully with a cotton ball. Rinse the wafer with alcohol at the end to ensure there is no residue.

Step S204, forming a passivation layer 304 covering the spin-valve GMR film structure and metal wires, as shown in FIG. 3c.

Choose PECVD to prepare the SiO2 passivation layer 304 under the condition of 200°C, and grow SiO2 twice, each time growing 100nm. The advantage of growing SiO2 twice is that the "holes" in the upper and lower layers of SiO2 can be staggered to reduce the permeability of ions in the solution.

Step S205 , forming a bioaffinity layer 305 on the passivation layer 304 .

Photolithography is performed on the passivation layer 304 to form the required Au region for the biological layer. Before sputtering Au, sputter The Ti acts as an adhesion layer so that the adhesion of Au to the passivation layer is stronger. The Au layer bio-affinity region is formed by the positive photoresist stripping process.

Step S206 , etching the passivation layer 304 and the bioaffinity layer 305 to expose a part of the metal wire 303 .

Step S2061, photolithography IV, spin-coating SU-8 glue 306 as a reinforced passivation layer 304, as shown in FIG. 3d.

Spin-coat a layer of SU-8 glue 306 with a thickness of 2 μm on the surface of the sensor as a protective layer, and form a pattern after exposure and development, exposing the bioaffinity area of the Au layer and the Pad pattern. Put the silicon wafer coated with SU-8 into the oven, and let the oven slowly heat up to 180°C to prevent SU-8 from bursting and cracking. After heating for ten minutes, slowly lower the temperature of the oven to room temperature, take out the silicon wafer, and complete the curing of the SU-8 glue on the surface of the sensor.

In one embodiment of the present invention, can also replace SU-8 glue with silicon nitride, promptly use the composite passivation layer of silicon dioxide and silicon nitride, grow by PECVD method, in two kinds of film thicknesses all are big enough Under certain circumstances, it can also meet the requirements of protecting the internal structure of the sensor and the sensitivity of biological detection.

Step S2062, wet etching to expose the Pad.

Since the Au and SU-8 formed in the two-step process of step S204 and step S205 form a natural corrosion resistance layer, there is no need to spin-coat photoresist in this step process to assist the corrosion of the passivation layer SiO2, and the silicon wafer Soak in corrosive liquid for corrosion.

In one embodiment of the present invention, the composition of the etching solution is NH4F:HF:H2O=5:1:1.

According to the manufacturing method of the biosensor according to the embodiment of the present invention, the composite passivation layer structure is adopted, which not only effectively protects the surface of the sensor from solution erosion, but also ensures the requirements of the detection sensitivity of the system, and the manufacturing technology is stable and the operation steps are simple, which can mass production applications.

The multi-channel scanning circuit detection system provided by the embodiment of the present invention is described below with reference to FIG. 4 . The multi-channel scanning circuit detection system of the embodiment of the present invention can be used to process the sensing signal of the spin valve GMR biosensor. Specifically, the spin-valve GMR biosensor will produce a change in magnetoresistance response to the edge field of the magnetic ball due to the giant magnetic effect. The multi-channel scanning circuit detection system of the embodiment of the present invention converts the above magnetoresistance change into a voltage signal, and amplifies and filters the voltage signal. Wherein, the multi-channel scanning circuit detection system of the embodiment of the present invention includes a plurality of channels, and is controlled by a LabVIEW program to realize real-time multi-channel scanning detection.

As shown in Figure 4, the multi-channel scanning circuit detection system provided by the embodiment of the present invention includes: the biosensor provided by the embodiment of the second aspect of the present invention, a multi-channel detector 401, a multiplexer 403, a low noise amplifier 404, a Pass filter 405 and LabVIEW controller 402. Among them, the multi-channel detector 401 is connected to the biosensor, the multiplexer 403 is connected to the multi-channel detector 401, the low-noise amplifier (LNA) 404 is connected to the multiplexer (MUX) 403, and the band-pass filter (BPF) 405 is connected with the low noise amplifier 404, and the LabVIEW controller is used to control the multi-channel detector 401 and the multiplexer 403.

In one embodiment of the present invention, the multi-channel detector 401 includes 8 detection channels, namely Chan1, Chan2, Chan3, Chan4, Chan5, Chan6, Chan7 and Chan8. Specifically, the multi-channel detector 401 monitors the voltage signals at both ends of the 8 groups of Wheatstone bridges through 8 different signal channels. When the magnetoresistance of the GMR sensing unit of the biosensor changes, the multiplexer 403 is scanned and strobed through the LavVIEW program, and the eight signal channels will output voltage signals in turn, and then the low-noise amplifier 404 is used to output the weak output of the bridge. The signal is amplified. And use the band-pass filter 405 to filter out the required frequency of the AC signal from other noises, and display it on the computer.

Multiple GMR Wheatstone bridge channels are designed on the biosensor and the corresponding signal detection circuit. The GMR sensor units of the above channels are scattered on the chip surface. The multi-channel data can reflect the uniformity of biomolecules immobilized on the surface. And the corresponding impact of this irregular distribution on the sensor.

In yet another embodiment of the present invention, the multi-channel scanning circuit detection system of the embodiment of the present invention further includes an analog/digital converter 406, which is used to convert the analog signal output by the band-pass filter 405 into a digital signal for display by a computer Come out for user reference.

The LabVIEW controller 402 performs scanning control on the multi-channel detector 401 , the multiplexer 403 , the low noise amplifier 404 and the band-pass filter 405 . Among them, the control signals of the multi-channel detector 401, the multiplexer 403, the low-noise amplifier 404 and the band-pass filter 405 are all provided by the LabVIEW controller 402 through the parallel port line. The 8 data bits are respectively given to multiple chips in the detection circuit, including the multiplexer 403, the low-noise amplifier 404 and the band-pass filter 405 to allocate addresses and data.

The LabVIEW controller 402 can directly input the parameters that need to be controlled on the front panel. After running the program, each parameter will be transferred to the rear panel to perform various calculations and controls, and write the control codes into the parallel port in an orderly manner. , to control the state and output of each component.

In one embodiment of the present invention, the LabVIEW controller 402 realizes real-time scanning detection of each chip by setting "time slices" for multiple channels. The LabVIEW controller 402 can complete the signal acquisition and amplification and filtering output of the corresponding channel within a "time slice", and the signal data can be displayed and recorded in real time within the "time slice". After the "time slice" is used up, the LabVIEW controller 402 automatically switches the strobe signal of the multiplexer 403 to the next channel, thereby realizing the alternate scanning detection of multiple channels.

In yet another embodiment of the present invention, the multi-channel scanning circuit detection system provided by the embodiment of the present invention can also use a single-chip microcomputer instead of the LabVIEW controller 402 to realize the scanning control of the multiplexer, multiplex detector and low-noise amplifier, That is, the scanning control of each component is realized by using the interface design and programming control design of the single-chip microcomputer, which is easier to implement than the LabVIEW program, and the output signal can also be displayed in real time through the digital tube.

The multi-channel scanning circuit detection system according to the embodiment of the present invention has the characteristics of high signal-to-noise ratio, high sensitivity, and good stability, and can accurately reflect the influence of the magnetic sensor on the magnetoresistance change of the fringe field of the nano-magnetic ball. In addition, the multi-channel scanning detection method is adopted, and LABVIEW is used to realize the control, which can effectively control the system status and output, and display the output voltage signal in real time. The technology is stable, the operation steps are simple, and it can be mass-produced and applied.

The biological detection method according to the embodiment of the present invention will be described below with reference to FIG. 5 and FIG. 6 . The biological detection method of the embodiment of the present invention adopts nano-magnetic labeling technology, and uses nano-magnetic spheres to label antigen molecules. The biosensor sensing magnetic balls composed of spin-valve giant magnetoresistance GMR film structures can indirectly sense antigen molecules, and then carry out molecular analysis of various immune active molecules labeled with nano-magnetic balls immobilized on the surface of biosensors through biochemical reactions. Concentration detection. Specifically, the concentration information of the biomolecules to be tested is correlated with the concentration of the labeled magnetic spheres, and the edge field response signals of the nano-magnetic spheres marked on the biomolecules are collected through the biosensor, and then the edge field signals of the magnetic spheres are transformed by the giant magnetic effect GMR It is the magnetoresistance change signal, and finally the magnetoresistance change acquisition is converted into an easy-to-handle and observe voltage signal, thereby indirectly reflecting the concentration information of the biomolecules to be measured. This bioassay can be applied to a variety of proteins, nucleic acids, and other biomolecules.

Step S501, combining the biomolecules to be tested with magnetic nanospheres to form biomolecules to be tested with magnetic labels.

Step S5011, forming a bioaffinity layer on the surface of the biosensor.

A thiol compound layer was self-assembled on the surface of the Au film of the bioaffinity layer of the biosensor (GMRspin-vavlesensor) as the bioaffinity layer (Au-thiolSAM).

The biosensor is designed as 8 half-bridge channels and 2 full-bridge channels, each channel has a signal unit and a reference unit, and shares the signal input terminal. For each signal unit, magnetoresistance films with the same area are connected in parallel or in series. After the process flow is completed, the silicon chip of the GMR sensor is diced, bonded and packaged with a DIP24 tube. Since the biosensor will perform biochemical experiments in a liquid environment, glue is applied to the wires around the biosensor to protect the wires and pads so as not to burn the chip.

Step S5012, binding the primary antibody of the biomolecule to be tested to the bioaffinity layer.

Conjugate primary antibody and sulfhydryl compound.

Step S5013, combining the antigen of the biomolecule to be tested with an antibody.

Step S5014, combining the biotin-linked secondary antibody of the biomolecule to be tested with the antigen.

Step S5015, binding the streptavidin-linked magnetic nanospheres to the biotin on the surface of the secondary antibody.

Step S502, immobilizing the biomolecules to be tested with magnetic labels on the surface of the biosensor provided in the above embodiments of the present invention.

Step S503 , detecting the fringe field response signal of the magnetic nanosphere, and converting the fringe field response signal of the magnetic nanosphere into a corresponding voltage signal to detect the concentration of the biomolecule to be detected.

In one embodiment of the present invention, the following steps are further included: using a multi-channel scanning circuit detection system to detect the concentration curves of multiple biomolecules to be tested; and estimating the corresponding concentration interval of the biomolecules to be tested according to the concentration curves.

In order to facilitate the immobilization experiment of biomolecules on the surface of the sensor, the biosensor and the multi-channel scanning circuit detection system were designed on two PCB boards respectively. When the system was integrated, the transfer board was connected to the motherboard of the real-time multi-channel scanning circuit detection system. After the system is initialized, the detection data of each channel of the AC detection system can be displayed in real time. Compared with the previous data, the signal corresponding curve of the sensor under different biomolecule concentrations can be obtained, and the concentration curve can be used to estimate the biomolecules of unknown concentration. concentration range.

Specifically, the GMR biosensor chip is packaged through a special shell, and a biochemical reaction pool with sufficient space is formed right above the chip. Then the tube shell is fixed on the corresponding base on the PCB board of the multi-channel scanning circuit detection system. Such an integration method and detection platform can detect and estimate the concentration of various biomolecules.

According to the biological detection method of the embodiment of the present invention, nano magnetic balls are used to label immunologically active molecules, and the response signal of the GMR magnetic sensor to the magnetic balls is used to reflect the detection method of the concentration of biomolecules. This detection platform can measure the concentration of various biomolecules. The detection and interval estimation, and the technology is stable, the operation steps are simple, and can be applied in mass production.

Any process or method descriptions in flowcharts or otherwise described herein may be understood to represent modules, segments or portions of code comprising one or more executable instructions for implementing specific logical functions or steps of the process , and the scope of preferred embodiments of the invention includes alternative implementations in which functions may be performed out of the order shown or discussed, including substantially concurrently or in reverse order depending on the functions involved, which shall It is understood by those skilled in the art to which the embodiments of the present invention pertain.

The logic and/or steps represented in the flowcharts or otherwise described herein, for example, can be considered as a sequenced listing of executable instructions for implementing logical functions, can be embodied in any computer-readable medium, For use with an instruction execution system, device, or device (such as a computer-based system, a system including a processor, or other systems that can fetch instructions from an instruction execution system, device, or device and execute instructions), or in conjunction with such an instruction execution system, device or equipment for use. For the purposes of this specification, a "computer-readable medium" may be any device that can contain, store, communicate, propagate or transmit a program for use in or in conjunction with an instruction execution system, device or device. More specific examples (non-exhaustive list) of computer-readable media include the following: electrical connection with one or more wires (electronic device), portable computer disk case (magnetic device), random access memory (RAM), Read Only Memory (ROM), Erasable and Editable Read Only Memory (EPROM or Flash Memory), Fiber Optic Devices, and Portable Compact Disc Read Only Memory (CDROM). In addition, the computer-readable medium may even be paper or other suitable medium on which the program can be printed, since the program can be read, for example, by optically scanning the paper or other medium, followed by editing, interpretation or other suitable processing if necessary. The program is processed electronically and stored in computer memory.

It should be understood that various parts of the present invention can be realized by hardware, software, firmware or their combination. In the embodiments described above, various steps or methods may be implemented by software or firmware stored in memory and executed by a suitable instruction execution system. For example, if implemented in hardware, as in another embodiment, it can be implemented by any one or combination of the following techniques known in the art: Discrete logic circuits, ASICs with suitable combinational logic gates, Programmable Gate Arrays (PGAs), Field Programmable Gate Arrays (FPGAs), etc.

Those of ordinary skill in the art can understand that all or part of the steps carried by the methods of the above embodiments can be completed by instructing related hardware through a program, and the program can be stored in a computer-readable storage medium. During execution, one or a combination of the steps of the method embodiments is included.

In addition, each functional unit in each embodiment of the present invention may be integrated into one processing module, each unit may exist separately physically, or two or more units may be integrated into one module. The above-mentioned integrated modules can be implemented in the form of hardware or in the form of software function modules. If the integrated modules are realized in the form of software function modules and sold or used as independent products, they can also be stored in a computer-readable storage medium.

The storage medium mentioned above may be a read-only memory, a magnetic disk or an optical disk, and the like.

In the description of this specification, descriptions referring to the terms "one embodiment", "some embodiments", "example", "specific examples", or "some examples" mean that specific features described in connection with the embodiment or example , structure, material or characteristic is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials or characteristics described may be combined in any suitable manner in any one or more embodiments or examples.

Although the embodiments of the present invention have been shown and described, those skilled in the art can understand that various changes, modifications and substitutions can be made to these embodiments without departing from the principle and spirit of the present invention. and modifications, the scope of the invention is defined by the appended claims and their equivalents.

Claims (12)

1. a Spin Valve giant magnetoresistance GMR membrane structure, it is characterised in that including:

Substrate, described substrate is the glass after polishing；

Forming the cushion in described substrate, described cushion includes β-Ta, and the thickness of described cushion is 5nm；

Being sequentially formed at the synthetic free layer on described cushion, the thickness of described synthetic free layer is 5.5nm, and described synthetic free layer includes the first free layer and the second free layer, and wherein, described first free layer includes NiFe, and described second free layer includes CoFe；

Forming the sealing coat on described synthetic free layer, described sealing coat is non-magnetic material, and the thickness of described sealing coat is 1.8nm；

Forming the nailed layer on described sealing coat, described nailed layer includes CoFe, and the thickness of described nailed layer is 3.5nm；

Forming the pinning layer on described nailed layer, described pinning layer includes IrMn, and the thickness of described pinning layer is 11nm；And

Forming the cover layer on described pinning layer, the thickness of described cover layer is 3nm, and described cover layer includes Ta.

2. a biosensor, it is characterised in that including:

Spin Valve giant magnetoresistance GMR membrane structure as claimed in claim 1；

It is formed at the plain conductor that described Spin Valve giant magnetoresistance GMR membrane structure is connected；

Cover described Spin Valve giant magnetoresistance GMR membrane structure and partly cover the passivation layer of described plain conductor；And

Form the affine layer of biology on described passivation layer.

3. biosensor as claimed in claim 2, it is characterised in that described passivation layer is SiO₂。

4. biosensor as claimed in claim 2, it is characterised in that described biology is affine, and layer is Au.

5. the manufacture method of a biosensor, it is characterised in that comprise the following steps:

Substrate is provided, and described substrate is carried out；

Form Spin Valve giant magnetoresistance GMR thin film in described substrate, and etch described Spin Valve giant magnetoresistance GMR thin film to form Spin Valve giant magnetoresistance GMR membrane structure as claimed in claim 1；

It is formed at the plain conductor that described Spin Valve giant magnetoresistance GMR membrane structure is connected；

Form the passivation layer covering described Spin Valve giant magnetoresistance GMR membrane structure and described plain conductor；

Biological affine layer is formed on described passivation layer；And

Etch described passivation layer and the affine layer of described biology to expose a part for described plain conductor.

6. the manufacture method of biosensor as claimed in claim 5, it is characterised in that also include:

Aoxidize to form dielectric substrate to described substrate.

7. the manufacture method of biosensor as claimed in claim 5, it is characterised in that also include:

By ibl compartment of terrain, described Spin Valve giant magnetoresistance GMR thin film is performed etching.

8. the manufacture method of biosensor as claimed in claim 5, it is characterised in that described passivation layer is formed by twice PECVD.

9. a multi-channel scan circuit detection system, it is characterised in that including:

Biosensor as described in any one of claim 2-4；

Multichannel detector, described multichannel detector is connected with described biosensor；

MUX, described MUX is connected with described multichannel detector；

Low-noise amplifier, described low-noise amplifier is connected with described MUX；

Band filter, described band filter is connected with described low-noise amplifier；And

LabVIEW controller, described LabVIEW controller is for being controlled described multichannel detector and described MUX.

10. a biological detecting method, it is characterised in that comprise the following steps:

Undertaken biomolecule to be measured and nanoscale magnetic bead combining to form the biomolecule to be measured carrying magnetic marker；

The described biomolecule to be measured carrying magnetic marker is fixed on the surface of the biosensor according to any one of claim 2-4；And

Detect the fringing field response signal of described nanoscale magnetic bead, and the fringing field response signal of described nanoscale magnetic bead is converted to corresponding voltage signal to detect the concentration of described biomolecule to be measured.

11. biological detecting method as claimed in claim 10, it is characterised in that described biomolecule to be measured and nanoscale magnetic bead are combined, comprise the steps:

Biological affine layer is formed on the surface of the biosensor according to any one of described claim 2-4；

One antibody of described biomolecule to be measured is combined with the affine layer of described biology；

By the antigen of described biomolecule to be measured and a described antibodies；

Two antibody connecting the biomolecule described to be measured of biotin are combined with described antigen；

The described nanoscale magnetic bead connecting Streptavidin is combined with the biotin of described two antibody surface.

12. such as claim 10 or 11 biological detecting method, it is characterised in that also comprise the steps:

The multi-channel scan circuit detection system described in claim 9 is utilized to detect the concentration curve of multiple described biomolecule to be measured；

The concentration ranges of the biomolecule described to be measured of described correspondence is estimated according to described concentration curve.